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取代非环核苷混膦酸酯类衍生物的合成及生物活性

欧瑜, 傅晓钟, 查雨锋, 张顺, 苏航, 董永喜

欧瑜, 傅晓钟, 查雨锋, 张顺, 苏航, 董永喜. 取代非环核苷混膦酸酯类衍生物的合成及生物活性[J]. 中国药科大学学报, 2014, 45(6): 649-656. DOI: 10.11665/j.issn.1000-5048.20140605
引用本文: 欧瑜, 傅晓钟, 查雨锋, 张顺, 苏航, 董永喜. 取代非环核苷混膦酸酯类衍生物的合成及生物活性[J]. 中国药科大学学报, 2014, 45(6): 649-656. DOI: 10.11665/j.issn.1000-5048.20140605
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OU Yu, FU Xiaozhong, ZHA Yufeng, ZHANG Shun, SU Hang, DONG Yongxi. Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates[J]. Journal of China Pharmaceutical University, 2014, 45(6): 649-656. DOI: 10.11665/j.issn.1000-5048.20140605
Citation: OU Yu, FU Xiaozhong, ZHA Yufeng, ZHANG Shun, SU Hang, DONG Yongxi. Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates[J]. Journal of China Pharmaceutical University, 2014, 45(6): 649-656. DOI: 10.11665/j.issn.1000-5048.20140605
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取代非环核苷混膦酸酯类衍生物的合成及生物活性

  • 1.

    贵阳市妇幼保健院药剂科

  • 2.

    贵阳医学院药学院，民族药与中药开发应用教育部工程研究中心

基金项目: 国家自然科学基金资助项目(No.81460523)；贵州省优秀青年科技人才培养对象专项基金资助项目(No.2013-45)；贵州省社会发展攻关计划项目资助(No.2013-3031)

Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates

摘要

    摘要
  • 摘要: 为寻找抗乙肝病毒(HBV)取代非环核苷混膦酸酯有效的结构优化策略。以阿德福韦单L-氨基酸酯和单非甾体药物羧酸酯为先导化合物，结合核苷类似物阿巴卡韦与阿拉莫韦的结构特征，采用亚结构拼合原理设计并合成了6-取代嘌呤非环核苷膦酸单L-氨基酸酯、单非甾体药物羧酸酯前药( 9a~9l )，其结构经1H NMR，ESI-MS，ESI-HRMS确证。采用HepG2 2.2.15细胞株、HK-2细胞株进行了目标化合物抗HBV活性以及肾细胞毒性评价。结果表明，化合物 9a 具有较强的抗病毒活性与作用选择性(EC50 0.48 μmol/L，SI 763.72)，具有较低的肾细胞毒性以及较高的化学与酶学稳定性，值得进一步深入研究。
    Abstract: In order to find structural optimization strategy for substituted mixed phosphonates of acyclonucleoside phosphonates, mono L-amino acid ester, mono NSAID carboxylic ester prodrugs of adefovir was used as lead compound. Based on the structural features of abacavir and alamifovir, sub-structure combination method was used to introduce substituted phenylthio or amino fragments at 6-position of purine ring. Therefore, purine ring substituted acyclonucleside phosphonate mixed phosphonate ester derivatives( 9a-9l )were designed and synthesized, and their structures were confirmed by 1H NMR, ESI-MS, and ESI-HRMS. HepG2. 2. 2. 15 and HK-2 cell line were used for in vitro anti-HBV activity and renal cell toxicity evaluation models, respectively. Several compounds exhibited anti-HBV activity, of which compound 9a displayed the most potent antiviral activity with higher selectivity index(EC50 0. 48 μmol/L, SI 763. 72), lower renal cell toxicity, and higher chemical and enzymatic stability, making it a potential anti-HBV candidate for further investigation.
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    • 参考文献(13)
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  • 刊出日期:  2014-12-24

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